Background and Aims:Cirrhotic cardiomyopathy(CCM)is a significant complication of cirrhosis,but its progression and underlying mechanisms remain incompletely understood.This study aimed to investigate dynamic changes ...Background and Aims:Cirrhotic cardiomyopathy(CCM)is a significant complication of cirrhosis,but its progression and underlying mechanisms remain incompletely understood.This study aimed to investigate dynamic changes in cardiac function,pathology,inflammation,and mitochondrial damage in a mouse model of CCM,and to compare echocardiographic characteristics in patients with cirrhosis.Methods:Bile duct ligation was performed in male C57BL/6J mice to induce cirrhosis.Longitudinal analyses were conducted over eight weeks.Cardiac function was assessed using serum biomarkers,echocardiography,and electrocardiography.Pathology was examined with hematoxylin and eosin,Masson’s trichrome,Sirius Red,and wheat germ agglutinin staining.Western blotting and immunohistochemistry were used to detect markers of inflammation,fibrosis,apoptosis,and mitochondrial function.Cardiac and liver function markers were also evaluated in patients with cirrhosis.Results:Mice subjected to bile duct ligation developed progressive cardiac dysfunction,including reduced cardiac output and diastolic dysfunction(enddiastolic interventricular septal thickness,left ventricular internal diameters,stroke volume,and left ventricular end-diastolic volume decreased,whereas ejection fraction and fractional shortening increased),as well as cardiac atrophy.Myocardial apoptosis,inflammation(elevated tumor necrosis factor,interleukin-6,and p65),and fibrosis worsened over time.Mitochondrial injury was characterized by reduced carnitine palmitoyltransferase 1A and peroxisome proliferator-activated receptor alpha,with increased hexokinase 2,pyruvate kinase M2,and lactate dehydrogenase A.In patients with cirrhosis,impaired cardiac function and elevated brain natriuretic peptide levels correlated with total bilirubin.Conclusions:The progression of CCM is closely associated with cirrhosis severity and appears to be driven by myocardial atrophy,apoptosis,inflammation,fibrosis,and mitochondrial dysfunction.展开更多
Obeticholic acid(OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possi...Obeticholic acid(OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, D-galactosamine/LPS(GalN/LPS)-treated mice and cycloheximide/TNFα(CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell(HSC)activation/proliferation and prevented fibrosis. Elevated bile acid(BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.展开更多
基金financially supported by grants from the National Natural Science Foundation of China(82174063,82204703)the National Natural Science Foundation of Anhui Province(2008085MH287)the Anhui Province Traditional Chinese Medicine Inheritance and Innovation Scientific Research Project(2020cczd03).
文摘Background and Aims:Cirrhotic cardiomyopathy(CCM)is a significant complication of cirrhosis,but its progression and underlying mechanisms remain incompletely understood.This study aimed to investigate dynamic changes in cardiac function,pathology,inflammation,and mitochondrial damage in a mouse model of CCM,and to compare echocardiographic characteristics in patients with cirrhosis.Methods:Bile duct ligation was performed in male C57BL/6J mice to induce cirrhosis.Longitudinal analyses were conducted over eight weeks.Cardiac function was assessed using serum biomarkers,echocardiography,and electrocardiography.Pathology was examined with hematoxylin and eosin,Masson’s trichrome,Sirius Red,and wheat germ agglutinin staining.Western blotting and immunohistochemistry were used to detect markers of inflammation,fibrosis,apoptosis,and mitochondrial function.Cardiac and liver function markers were also evaluated in patients with cirrhosis.Results:Mice subjected to bile duct ligation developed progressive cardiac dysfunction,including reduced cardiac output and diastolic dysfunction(enddiastolic interventricular septal thickness,left ventricular internal diameters,stroke volume,and left ventricular end-diastolic volume decreased,whereas ejection fraction and fractional shortening increased),as well as cardiac atrophy.Myocardial apoptosis,inflammation(elevated tumor necrosis factor,interleukin-6,and p65),and fibrosis worsened over time.Mitochondrial injury was characterized by reduced carnitine palmitoyltransferase 1A and peroxisome proliferator-activated receptor alpha,with increased hexokinase 2,pyruvate kinase M2,and lactate dehydrogenase A.In patients with cirrhosis,impaired cardiac function and elevated brain natriuretic peptide levels correlated with total bilirubin.Conclusions:The progression of CCM is closely associated with cirrhosis severity and appears to be driven by myocardial atrophy,apoptosis,inflammation,fibrosis,and mitochondrial dysfunction.
基金supported by National Natural Science Foundation of China (grants 81430091, 81720108032, 81421005, 91429308 and 81603194)the Project for Major New Drug Innovation and Development (grant 2015ZX09501010 and 2017ZX09101003-002-003, China)+3 种基金Overseas Expertise Introduction Project for Discipline Innovation (G20582017001, China)"Double First Class" Initiative Project (CPU2018GF01 and CPU2018GF09, China)State Key Laboratory of Natural Medicines at China Pharmaceutical University (SKLNMZZCX201610 and SKLNMZZCX201801, China)China Postdoctoral Science Foundation (grants 2016M600455 and 2017T100423)
文摘Obeticholic acid(OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, D-galactosamine/LPS(GalN/LPS)-treated mice and cycloheximide/TNFα(CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell(HSC)activation/proliferation and prevented fibrosis. Elevated bile acid(BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.
